tbuckley/cabot-search huggingface dataset:
Effect of Noninvasive Airway Management of Comatose Patients With Acute Poisoning
Authors: Yonathan Freund, Damien Viglino, Marine Cachanado, Clémentine Cassard, Emmanuel Montassier, Bénedicte Douay, Jérémy Guenezan, Pierrick Le Borgne, Youri Yordanov, Armelle Severin, Mélanie Roussel, Matthieu Daniel, Adrien Marteau, Nicolas Peschanski, Dorian Teissandier, Richard Macrez, Julia Morere, Tahar Chouihed, Damien Roux, Frédéric Adnet, Ben Bloom, Anthony Chauvin, Tabassome Simon
Journal: JAMA (2023)

Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain.
Resident microbes shape the vaginal epithelial glycan landscape
Authors: Kavita Agarwal, Biswa Choudhury, Lloyd S. Robinson, Sydney R. Morrill, Yasmine Bouchibiti, Daisy Chilin-Fuentes, Sara B. Rosenthal, Kathleen M. Fisch, Jeffrey F. Peipert, Carlito B. Lebrilla, Jenifer E. Allsworth, Amanda L. Lewis, Warren G. Lewis
Journal: Science Translational Medicine (2023)

Epithelial cells are covered in carbohydrates (glycans). This glycan coat or "glycocalyx" interfaces directly with microbes, providing a protective barrier against potential pathogens. Bacterial vaginosis (BV) is a condition associated with adverse health outcomes in which bacteria reside in direct proximity to the vaginal epithelium. Some of these bacteria, including
Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2α in skeletal progenitor cells
Authors: Wendi Guo, Jiaul Hoque, Carolina J. Garcia Garcia, Kassandra V. Spiller, Abigail P. Leinroth, Vijitha Puviindran, Cahil K. Potnis, Kiana A. Gunn, Hunter Newman, Koji Ishikawa, Tara N. Fujimoto, Denae W. Neill, Abagail M. Delahoussaye, Nerissa T. Williams, David G. Kirsch, Matthew J. Hilton, Shyni Varghese, Cullen M. Taniguchi, Colleen Wu
Journal: Science Translational Medicine (2023)

Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor-expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2α (HIF-2α), thus suggesting a role for HIF-2α in the skeletal response to radiation. Here, we conditionally knocked out HIF-2α in leptin receptor-expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2α conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2α negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2α pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2α inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2α was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2α inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2α inhibitor to mouse bone, to increase on-target efficacy and reduce off-target toxicities. Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2α may represent a therapeutic approach for protecting bone during radiation therapy.
T cell responses to SARS-CoV-2 infection and vaccination are elevated in B cell deficiency and reduce risk of severe COVID-19
Authors: Reza Zonozi, Lucy C. Walters, Aaron Shulkin, Vivek Naranbhai, Pravarut Nithagon, Gabriel Sauvage, Clarety Kaeske, Katherine Cosgrove, Anusha Nathan, Rhoda Tano-Menka, Alton C. Gayton, Matthew A. Getz, Fernando Senjobe, Daniel Worrall, A. John Iafrate, Caroline Fromson, Sydney B. Montesi, Deepak A. Rao, Jeffrey A. Sparks, Zachary S. Wallace, Jocelyn R. Farmer, Bruce D. Walker, Richelle C. Charles, Karen Laliberte, John L. Niles, Gaurav D. Gaiha
Journal: Science Translational Medicine (2023)

Individuals with primary and pharmacologic B cell deficiencies have high rates of severe disease and mortality from coronavirus disease 2019 (COVID-19), but the immune responses and clinical outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination have yet to be fully defined. Here, we evaluate the cellular immune responses after both SARS-CoV-2 infection and vaccination in patients receiving the anti-CD20 therapy rituximab (RTX) and those with low B cell counts due to common variable immune deficiency (CVID) disease. Assessment of effector and memory CD4 + and CD8 + T cell responses to SARS-CoV-2 revealed elevated reactivity and proliferative capacity after both infection and vaccination in B cell–deficient individuals, particularly within the CD8 + T cell compartment, in comparison with healthy controls. Evaluation of clinical outcomes demonstrates that vaccination of RTX-treated individuals was associated with about 4.8-fold reduced odds of moderate or severe COVID-19 in the absence of vaccine-induced antibodies. Analysis of T cell differentiation demonstrates that RTX administration increases the relative frequency of naïve CD8 + T cells, potentially by depletion of CD8 + CD20 dim T cells, which are primarily of an effector memory or terminal effector memory (TEMRA) phenotype. However, this also leads to a reduction in preexisting antiviral T cell immunity. Collectively, these data indicate that individuals with B cell deficiencies have enhanced T cell immunity after both SARS-CoV-2 infection and vaccination that potentially accounts for reduced hospitalization and severe disease from subsequent SARS-CoV-2 infection.
Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease
Authors: Mohammed Repon Khan, Xiling Yin, Sung-Ung Kang, Jaba Mitra, Hu Wang, Taekyung Ryu, Saurav Brahmachari, Senthilkumar S. Karuppagounder, Yasuyoshi Kimura, Aanishaa Jhaldiyal, Hyun Hee Kim, Hao Gu, Rong Chen, Javier Redding-Ochoa, Juan Troncoso, Chan Hyun Na, Taekjip Ha, Valina L. Dawson, Ted M. Dawson
Journal: Science Translational Medicine (2023)

Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic α-synuclein interactome. We report that the highest biological processes that interacted with pathologic α-synuclein in mice included RNA processing and translation initiation. Regulation of catabolic processes that include autophagy were also identified. Pathologic α-synuclein was found to bind with the tuberous sclerosis protein 2 (TSC2) and to trigger the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which augmented mRNA translation and protein synthesis, leading to neurodegeneration. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescued the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the α-synuclein preformed fibril mouse model and Drosophila transgenic models of pathologic α-synuclein–induced degeneration. Pathologic α-synuclein furthermore led to a destabilization of the TSC1-TSC2 complex, which plays an important role in mTORC1 activity. Constitutive overexpression of TSC2 rescued motor deficits and neuropathology in α-synuclein flies. Biochemical examination of PD postmortem brain tissues also suggested deregulated mTORC1 signaling. These findings establish a connection between mRNA translation deregulation and mTORC1 pathway activation that is induced by pathologic α-synuclein in cellular and animal models of PD.
A T cell receptor β chain–directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity
Authors: Jonathan Hsu, Renee N. Donahue, Madan Katragadda, Jessica Lowry, Wei Huang, Karunya Srinivasan, Gurkan Guntas, Jian Tang, Roya Servattalab, Jacques Moisan, Yo-Ting Tsai, Allart Stoop, Sangeetha Palakurthi, Raj Chopra, Ke Liu, E. John Wherry, Zhen Su, James L. Gulley, Andrew Bayliffe, Jeffrey Schlom
Journal: Science Translational Medicine (2023)

Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline Vβ6 and Vβ10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR activation with costimulation to promote activation and expansion of αβ T cell subsets expressing distinct variable β (Vβ) TCR chains. In solution, STAR0602 binds IL-2 receptors in cis with Vβ6/Vβ10 TCRs on the same T cell, promoting expansion of human Vβ6 and Vβ10 CD4
Abstract 9690: Impact of Lesion Morphology on Angiographic and Clinical Outcomes in Patients With Chronic Total Occlusion After Successful Recanalization With Drug-eluting stents. A Multislice Computed Tomography Study
Authors: Tsuyoshi Ito, Etsuo Tsuchikane, Kenya Nasu, Masashi Kimura, Mitsuyasu Terashima, Yoshihisa Kinoshita, Maoto Habara, Takahiko Suzuki
Journal: Circulation (2013)

Background: Which subgroup of patients with chronic total occlusion (CTO) would be likely to derive a benefit from percutaneous coronary intervention (PCI) in the drug-eluting stent (DES) era has not yet been fully clarified. The aim of this study was to investigate the morphological characteristics of CTO associated with angiographic and clinical adverse outcomes after PCI with DES using multislice computed tomography (MSCT). Methods: In this study, 263 patients who underwent MSCT before CTO-PCI were followed clinically (the median follow-up was 4.0 years). Of these, 1 year follow-up angiography was performed in 203 patients. Lesion morphology was assessed with MSCT. Angiographic restenosis, reocclusion, and MACE (a composite of cardiac death, stent thrombosis and target lesion revascularization) were analyzed. Results: MACE was observed in 36 patients (13.6%). Occlusion length was longer (39.5±19.9 mm vs. 22.3±13.7 mm, p&lt;0.01), minimal vessel area was smaller (11.2±5.7mm 2 vs. 14.5±5.6mm 2 , p&lt;0.01) and severe calcification (involving &gt;50% of the coronary wall on cross sectional image) was more common (36% vs. 12%, p&lt;0.01) in the MACE group. In multivariate analysis, occlusion length (Odds ratio (OR); 1.06, p&lt;0.01), minimal vessel area (OR; 0.48, p&lt;0.01) and severe calcification (OR; 3.57, p&lt;0.01) were independent predictors of the MACE. Receiver operating characteristic analysis provided the cut-off value of occluded length (25.4 mm; area under the curve (AUC) 0.79; sensitivity 0.86, specificity 0.62) and minimal vessel area (11.9 mm 2 ; AUC 0.69; sensitivity 0.62, specificity 0.72) to predict the MACE. We defined occluded length &gt;25.4mm, minimal vessel area &lt;11.9mm 2 and severe calcification as CT-derived risk factors. Angiographic restenosis (60% vs. 12% vs. 7%, p&lt;0.01), reocclusion (29% vs. 2% vs. 2%, p&lt;0.01), and MACE (43% vs. 6% vs. 3%, p&lt;0.01) rates were significantly higher in patients with more than 2 risk factors than in those with 1 and 0. Conclusions: MSCT characteristics associated with angiographic and clinical adverse outcomes after CTO-PCI were occluded length, vessel area, and the degree of calcification.
Clonal haematopoiesis across the age spectrum of vasculitis patients with Takayasu’s arteritis, ANCA-associated vasculitis and giant cell arteritis
Authors: Fernanda Gutierrez-Rodrigues, Kristina V Wells, Adrianna I Jones, Dalton Hironaka, Cameron Rankin, Massimo Gadina, Keith A Sikora, Lemlem Alemu, Rodrigo T Calado, Kaitlin A Quinn, Bhavisha Patel, Neal S Young, Peter C Grayson
Journal: Annals of the Rheumatic Diseases (2023)

Objectives Ageing and inflammation are associated with clonal haematopoiesis (CH), the emergence of somatic mutations in haematopoietic cells. This study details CH in patients with systemic vasculitis in association with clinical, haematological and immunological parameters. Methods Patients with three forms of vasculitis were screened for CH in peripheral blood by error-corrected sequencing. Relative contributions of age and vasculitis on CH prevalence were calculated using multivariable logistic regression. Clonal hierarchies were assessed by proteogenomic single-cell DNA sequencing, and functional experiments were performed in association with CH status. Results Patients with Takayasu’s arteritis (TAK; n=70; mean age=33.2 years), antineutrophil cytoplasmic antibody-associated vasculitis (AAV; n=47; mean age=55.3 years) and giant cell arteritis (GCA; n=59; mean age=71.2 years) were studied. CH, most commonly in DNMT3A and TET2, was detected in 34% (60/176) of patients versus 18% (28/151) of age-matched controls (p&lt;0.01). Prevalence of CH was independently associated with age (standardised B=0.96, p&lt;0.01) and vasculitis (standardised B=0.46, p&lt;0.01), occurring in 61%, 32% and 13% of patients with GCA, AAV and TAK, respectively. Both branched and linear clonal trajectories showed myeloid-lineage bias, and CH was associated with markers of cellular activation. In GCA, mutations were detected in temporal artery biopsies, and clinical relapse correlated with CH in a dose-dependent relationship with clone size. Conclusions Age was more strongly associated with CH prevalence than inflammation in systemic vasculitis. Clonal profile was dominated by DNMT3A mutations which were associated with relapse in GCA. CH is not likely a primary causal factor in systemic vasculitis but may contribute to inflammation.
Delayed vaccine-induced CD8<sup>+</sup>T cell expansion by topoisomerase I inhibition mediates enhanced CD70-dependent tumor eradication
Authors: Tetje C van der Sluis, Floortje J van Haften, Suzanne van Duikeren, Iris N Pardieck, J Fréderique de Graaf, Ward Vleeshouwers, Koen van der Maaden, Cornelis J M Melief, Sjoerd H van der Burg, Ramon Arens
Journal: Journal for ImmunoTherapy of Cancer (2023)

The survival of patients with cervical cancer who are treated with cisplatin in conjunction with the topoisomerase I inhibitor topotecan is enhanced when compared with patients treated with only one of these chemotherapeutics. Moreover, cisplatin-based and T cell-based immunotherapy have been shown to synergize, resulting in stronger antitumor responses. Here, we interrogated whether topotecan could further enhance the synergy of cisplatin with T cell-based cancer immunotherapy. Mice bearing human papilloma virus 16 (HPV16) E6/E7-expressing TC-1 tumors were vaccinated with HPV16 E7 long peptides and additionally received chemotherapy consisting of cisplatin and topotecan. We performed an in-depth study of this combinatorial chemoimmunotherapy on the effector function and expansion/contraction kinetics of vaccine-induced CD8+ T cells in the peripheral blood and tumor microenvironment (TME). In addition, we interrogated the particular role of chemotherapy-induced upregulation of costimulatory ligands by tumor-infiltrated myeloid cells on T cell proliferation and survival. We show that E7 long peptide vaccination combined with cisplatin and topotecan, results in CD8+ T cell-dependent durable rejection of established tumors and 94% long-term survival. Although topotecan initially repressed the expansion of vaccine-induced CD8+ T cells, these cells eventually expanded vigorously, which was followed by delayed contraction. These effects associated with the induction of the proliferation marker Ki-67 and the antiapoptosis molecule Bcl-2 by intratumoral tumor-specific CD8+ T cells, which was regulated by topotecan-mediated upregulation of the costimulatory ligand CD70 on myeloid cells in the TME. Taken together, our data show that although treatment with cisplatin, topotecan and vaccination initially delays T cell expansion, this combinatorial therapy results eventually in a more robust T cell-mediated tumor eradication due to enhancement of costimulatory molecules in the TME.
Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors
Authors: Todd M Bauer, Armando Santoro, Chia-Chi Lin, Ignacio Garrido-Laguna, Markus Joerger, Richard Greil, Anna Spreafico, Thomas Yau, Maria-Elisabeth Goebeler, Marie Luise Hütter-Krönke, Antonella Perotti, Pierre-Eric Juif, Darlene Lu, Louise Barys, Viviana Cremasco, Marc Pelletier, Helen Evans, Claire Fabre, Toshikiko Doi
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors. Methods Patients received NIS793 (0.3–1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3–30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20–30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). Results Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-β target genes and signatures and increased immune signatures. Conclusions In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-β pathway inhibition. Trial registration number NCT02947165 .
TP53/mTORC1-mediated bidirectional regulation of PD-L1 modulates immune evasion in hepatocellular carcinoma
Authors: Jiongjie Yu, Sunbin Ling, Jiachen Hong, Lincheng Zhang, Wei Zhou, Lu Yin, Shengjun Xu, Qingyang Que, Yongfeng Wu, Qifan Zhan, Jiaqi Bao, Nan Xu, Yuchen Liu, Kangchen Chen, Xuyong Wei, Zhikun Liu, Tingting Feng, Lin Zhou, Haiyang Xie, Shuai Wang, Jimin Liu, Shusen Zheng, Xiao Xu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immunotherapy has facilitated great breakthroughs in the treatment of hepatocellular carcinoma (HCC). However, the efficacy and response rate of immunotherapy are limited and vary among different patients with HCC. TP53 mutation substantially affects the expression of immune checkpoint molecules in multiple cancers. However, the regulatory relationship between programmed death ligand 1 (PD-L1) and TP53 is poorly studied in HCC. We aimed to elucidate the regulatory mechanism of PD-L1 in HCC with different TP53 statuses and to assess its role in modulating immune evasion in HCC. Methods HCC mouse models and cell lines with different TP53 statuses were constructed. PD-L1 levels were detected by PCR, western blotting and flow cytometry. RNA-seqencing, immunoprecipitation, chromatin immunoprecipitation and transmission electron microscopy were used to elucidate the regulatory mechanism in HCC with different TP53 status. HCC mouse models and patient with HCC samples were analyzed to demonstrate the preclinical and clinical significance of the findings. Results We report that loss of p53 promoted PD-L1 expression and reduced CD8 + T-cell infiltration in patient with HCC samples and mouse models. Mammalian target of rapamycin (mTOR) pathway was activated in p53-loss-of-function HCC or after knocking down TP53. The transcription factor E2F1 was found to bind to the p53 protein in TP53 wild-type HCC cells, and inhibiting mammalian target of rapamycin complex 1 (mTORC1) disrupted this binding and enhanced E2F1 translocation to the nucleus, where it bound to the PD-L1 promoter and transcriptionally upregulated PD-L1. In p53-loss-of-function HCC cells, autophagosomes were activated after mTORC1 suppression, promoting the degradation of PD-L1 protein. The combination of mTOR inhibitor and anti-PD-L1 antibody enhanced CD8 + T-cell infiltration and tumor suppression in TP53 wild-type HCC mouse models, but no benefit was observed in p53-loss-of-function HCC mouse models. In patients with TP53 wild-type HCC, PD-L1 levels were significantly higher in the high E2F1 group than in the low E2F1 group, and the low E2F1 level group had significantly superior survival. Conclusion We revealed the bidirectional regulatory mechanism of PD-L1 mediated by TP53/mTORC1 in HCC. The combination of mTOR inhibitor and anti-PD-L1 antibody could be a novel precise immunotherapy scheme for TP53 wild-type HCC.
DMSA-coated IONPs trigger oxidative stress, mitochondrial metabolic reprograming and changes in mitochondrial disposition, hindering cell cycle progression of cancer cells
Authors: Neus Daviu, Yadileiny Portilla, Marta Gómez de Cedrón, Ana Ramírez de Molina, Domingo F. Barber
Journal: Biomaterials (2023)

There is increasing interest in modulating the redox homeostasis of tumors since high levels of reactive oxygen species (ROS) make them more vulnerable to changes in these species. Nanomedicine offers promise in this context as such applications may provoke biological responses that induce ROS production. Indeed, iron oxide nanoparticles (IONPs) can induce ROS accumulation through the so-called Fenton reaction of iron, further augmenting the ROS in tumors and overloading the antioxidant system beyond its capacity, thereby driving oxidative stress to a level that is incompatible with cell survival. Here, three different coatings for IONPs were compared to assess their intrinsic capacity to induce ROS production in cells. Of these coatings, dimercaptosuccinic acid-coated IONPs (DMSA-NPs) provoked the strongest ROS production, which was associated with the ability to reprogram the metabolism of cancer cells. This latter phenomenon involved shutting-down oxidative phosphorylation (OXPHOS), shifting mitochondrial morphology towards a more elongated phenotype, reducing the total mitochondrial mass and ultimately, blocking cell proliferation by inducing G0/G1 cell cycle arrest. Consequently, the data obtained highlights the importance of studying the chemical properties of IONPs, presenting DMSA-NPs as a novel tool to induce oxidative stress in cancer cells and alter their cell fate.